Recent preclinical and clinical studies suggest that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) was effective in treatment-resistant major depression. Ketamine resulted in rapid, robust and relatively sustained antidepressant effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. The current protocol consists of 3 primary studies designed to address 3 major questions, study 2 and 3 are still ongoing and subjects are actively being recruited to participate in these studies: Study 1 (Rapid improvement research in unipolar depression) OBJECTIVE: To determine whether a rapid antidepressant effect can be achieved with an antagonist at the N-methyl-D-aspartate receptor in subjects with major depression. DESIGN: A randomized, placebo-controlled, double-blind crossover study. SETTING: Mood Disorders Research Unit at the National Institute of Mental Health. PATIENTS: Eighteen subjects with DSM-IV major depression (treatment resistant). INTERVENTIONS: After a 2-week drug-free period, subjects were given an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart. RESULTS: Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection, which remained significant throughout the following week. The effect size for the drug difference was very large (d = 1.46 95% confidence interval, 0.91-2.01) after 24 hours and moderate to large (d = 0.68 95% confidence interval, 0.13-1.23) after 1 week. Of the 17 subjects treated with ketamine, 71% met response and 29% met remission criteria the day following ketamine infusion. Thirty-five percent of subjects maintained response for at least 1 week. CONCLUSIONS: Robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist;onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. There is now an ongoing study with subunit selective NMDA antagonists (NR2A and NR2B). Study 2 (Rapid improvement research in bipolar depression) Does the NMDA antagonist ketamine produce rapid antidepressant effects in patients with treatment-resistant bipolar depression? Patients ages 18 to 65 years with treatment-resistant bipolar depression are actively being recruited in a double-blind crossover study and are receiving either intravenous ketamine or saline solution added to a mood stabilizer (lithium or valproate). The efficacy component of the study is completed and the data are being analyzed. The study remains open for active recruitment as more subjects are required to complete the neurophysiological (MEG, PSG, PET substudies) in search of biomarkers of response. Study 3 (Rapid and sustained improvement research in unipolar depression) Does riluzole (an inhibitor of glutamate release) prevent relapse in patients with treatment-resistant major depression who have rapidly responded to a single intravenous dose of ketamine? Patients ages 18 to 65 years with treatment-resistant major (unipolar) depression who have rapidly responded to a single intravenous dose of ketamine are then randomized to receive in a double-blind study with either riluzole or placebo to determine if the rapid response obtained can be sustained. The study is still actively recruiting study participants. The results from this study are not yet available because the study has not yet been completed. Our primary hypotheses for these studies are: 1) rapid response (same or next day) can be achieved in patients with treatment-resistant major (unipolar) depression, 2) rapid response (same or next day) can be achieved in patients with treatment-resistant bipolar depression, and 3) rapid response (same or next day) can be sustained in patients with treatment-resistant unipolar depression. Other aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics), and 3) to test other glutamatergic modulators in mood disorders that target NR2A and NR2B. Results in the past year: 1) A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression.Existing therapies for bipolar depression have a considerable lag of onset of action. Pharmacological strategies that produce rapid antidepressant effects-for instance, within a few hours or days-would have an enormous impact on patient care and public health. OBJECTIVE: To determine whether an N-methyl-D-aspartate-receptor antagonist produces rapid antidepressant effects in subjects with bipolar depression. DESIGN: A randomized, placebo-controlled, double-blind, crossover, add-on study. INTERVENTIONS: Subjects maintained at therapeutic levels of lithium or valproate received an intravenous infusion of either ketamine hydrochloride (0.5 mg/kg) or placebo on 2 test days 2 weeks apart. MAIN OUTCOME MEASURES: Change in Montgomery-Asberg Depression Rating Scale primary efficacy measure scores. RESULTS: Within 40 minutes, depressive symptoms significantly improved in subjects receiving ketamine compared with placebo (d = 0.52;this improvement remained significant through day 3. The drug difference effect size was largest at day 2 (d = 0.80). Seventy-one percent of subjects responded to ketamine and 6% responded to placebo at some point during the trial. CONCLUSION: In patients with treatment-resistant bipolar depression, robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist. 2) Abnormal hippocampal functioning and impaired spatial navigation in depressed individuals: Dysfunction of the hippocampus has long been suspected to be a key component of the pathophysiology of major depressive disorder. Despite evidence of hippocampal structural abnormalities in depressed patients, abnormal hippocampal functioning has not been demonstrated. We examined the link of spatial navigation deficits previously documented in depressed patients to abnormal hippocampal functioning using a virtual reality navigation task. Whole-head magnetoencephalography (MEG) recordings were collected while participants navigated a virtual Morris water maze to find a hidden platform;navigation to a visible platform served as a control condition. Depressed patients showed impaired spatial navigation. Dysfunction of right anterior hippocampus and parahippocampal cortices may underlie this deficit and stem from structural abnormalities commonly found in depressed patients. 3) Anterior cingulate desynchronization and functional connectivity with the amygdala during a working memory task predict rapid antidepressant response to ketamine. Patients who showed the least engagement of the pgACC in response to increased working memory load showed the greatest symptomatic improvement within 4 h of ketamine administration. Pretreatment functional connectivity between the pgACC and the left amygdala was negatively correlated with antidepressant symptom change. These data implicate the pgACC and its putative interaction with the amygdala in predicting antidepressant response to ketamine in a working memory task context.